Telomeres are dynamic DNA-protein complexes that protect the ends of linear chromosomes. Most telomeric DNA is synthesized by the enzyme telomerase. While most somatic cells do not express telomerase and therefore have limited life span,cancer cells can bypass the crisis either through telomerase reactivation or through an alternative recombination pathway for telomere lengthening (ALT). I will talk about our recent findings on telomere replication by telomerase activation/inactivation and ALT.
　　 We demonstrated that telomerase is mainly activated by Cdk1/Tel1/Mec1 on telomeric binding protein Cdc13 from late S to G2 phase of the cell cycle.Hypernegatively charged domain of Cdc13 contributed by Cdk1, Tel1 and Mec1 may provide an optimal interface to recruit the potential positively charged domain near the amino acid 444 lysine residue of Est1 in the telomerase complex. PP2A phosphatase and Aurora kinase coordinately inhibit the function of telomerase.
Differential and additive actions of PP2A phosphatase and Aurora kinase on Cdc13 limit telomerase action by removing active telomerase from telomeres at G2/M phase.
　　 Moreover, our previous studies have indicated that yeast Sgs1 and Top3 may work together to remove highly negative supercoils that are generated from telomere recombination. However, the mechanism by which cells eradicate highly positive supercoils during recombination remains unclear. We demonstrate that Top2 is involved in telomere-telomere recombination, perhaps by resolving the highly positive supercoil structure at the front of the helicase. Inhibition of topoisomerase II may be a promising therapeutic approach that can be used to prevent cell proliferation in ALT-type cancer cells.